Strategies for Developing Effective Radioimmunotherapy for Solid Tumors I

Single-agent radioimmunotherapy (RIT) has proven efficacy as a treatment for hematological malignancies, particularly non-Hodgkin's lymphoma. Although promising, RIT has been less effective for solid tumors, in part because they are less radiosensitive. Bone marrow transplantation permits the administration of larger radiopharmaceutical doses, but the results of bone marrow transplantation-supported RIT for solid tumors have been marginal. The purpose of this publication is to provide an overview of promising RIT strategies for solid tumors. It is apparent that combination therapy is required, but optimization of the radiopharmaceutical should be the first step. Metallic radionuclides provide higher tumor radiation doses but not necessarily an improved therapeutic index, that is, the ratio of tumor:normal tissue radiation doses. Biodegradable peptide linkers between the chelated metal and the antibody improve the therapeutic index. Further improvements depend on identification of synergistic therapies which recognize that: (a) continuous, low-dose radionuclide therapy acts through apoptosis; and (b) apoptosis is often blocked because most tumors have ineffective p53 and increased Bcl-2. Taxanes are particularly attractive as synergistic agents for RIT because they induce cell cycle arrest in the radiosensitive G2-M phase and p53-independent apoptosis. Optimal sequence and timing for combined modality RIT are critical to achieve synergy. Data from preclinical and clinical studies will be reviewed to illustrate the potential of these strategies.